Bulk storage, freezing, and transfer are important steps which ensure that the final product is safely and promptly delivered to fill–finish sites and patients. Current bulk freeze-thaw practices use predominantly stainless steel systems. Unfortunately, stainless steel bulk freeze-thaw systems have their share of disadvantages. This article addresses Genentech's evaluation of single-use technologies for bulk freeze-thaw, storage, and transportation, including operational and functional testing, the mechanical properties of film, controlled freezing, and the risks involved in bulk shipping.

Nalgene, Inc.

Although disposable bioprocess containers (BPCs) are increasingly being welcomed into biotech facilities, plant managers have not been as quick to introduce disposable bulk freeze-thaw applications. Bulk storage, freezing, and transfer are important steps which ensure that the final product is safely and promptly delivered to fill–finish sites and patients.

As with other traditional manufacturing processes, current bulk freeze-thaw practices predominantly use stainless steel systems. Unfortunately, stainless steel bulk freeze-thaw systems have their share of disadvantages. From integrity testing and passivation challenges to continued upkeep and shipping validation, the number of man hours and support teams needed to sustain these stainless steel systems are high. However, as disposables move more into mainstream manufacturing, so too will disposable bulk freeze-thaw systems.

Storage Hold Process and Transporting Bulk

As it becomes compulsory to lengthen the lifetime of a protein product to reach patients worldwide, considerable effort and thought must go into the storage hold process. One option for bulk protein storage is holding the product in a liquid-state, either in a stainless steel tank or a disposable container. Although a viable option, the use of liquid-state storage has its own drawbacks. First, proteins may aggregate, resulting in product loss. Second, oxidation may cause some spontaneous reactions that would be detrimental to the bulk. Regardless of these concerns, there has been data that proves that this option may be suitable under certain conditions.1

Sartorius-Stedim's CryoFin

A less risky method for transporting bulk is through freezing, which slows down aggregation and oxidation to the point where they become less of a concern. Freezer systems used in the biopharmaceutical industry vary depending on the type and amount of product, but bulk traditionally is frozen in scalable containers ranging from small plastic bottles to large stainless steel tanks.

One example of a stainless steel freeze-thaw system would be Sartorius-Stedim Biotech's CryoFin. CryoFin cryopreservation technology consists of several separate components that include CryoVessels, thermal control units, and mixers. The freeze-thaw is controlled by active and passive heat transfer surfaces and is specifically designed for large-scale freezing of biotherapeutics. Although this system is novel and offers valuable flexibility to both the manufacturers and clients, it has some drawbacks. For example, because of its need to be tested and validated before use for sterile hold and other sampling and validation qualifications (which could take months or even years), by the time a stainless steel system is commissioned, the particular campaign in which the system might have been useful may have already been completed. Furthermore, the amount of capital necessary to invest in such a system is significant compared to equivalent disposable systems.

Sartorius-Stedim's 6L Celsius flexible freeze and thaw clamshell

Another option would be for bulk to be frozen and transported in disposable BPCs. An example of this application would be a container developed by Thermo Fisher Scientific. Using their HyQ CX5-14 film, Thermo Fisher Scientific's single-use bioprocess container system was developed and tested to satisfy certain important characteristics that all containers systems must require. Furthermore, integrity tests were done on these containers when they were frozen and transported while lying flat, in the hanging position, and during repeated freeze and thaw cycles. The test results indicated that all the units maintained fluid integrity and could be used as an alternative to stainless steel that negates the testing that stainless steel systems require.